PROJECT SUMMARY Accurate diagnosis and prognostication of patients with Parkinson?s disease (PD) remains challenging and precludes the most effective patient care. In addition, no disease modifying therapy for PD has been identified. Although the NINDS and other PD patient advocacy groups such as the Michael J. Fox Foundation have recognized the need for both diagnostic and prognostic PD biomarkers, no such biomarkers have been validated thus far. This Clinical Research Project will use immunoblot testing of serum-derived L1CAM+ exosomes to determine if specific molecules in the c-Abl pathway are potential PD diagnostic or progression biomarkers. The markers we have collected designated as ?c-Abl pathway molecules? are part of the non-receptor tyrosine kinase c-Abl signaling cascade. We hypothesize that the pathway begins with activation of c-Abl by pathologic ?-synuclein, which in turn phosphorylates parkin on tyrosine (Y) 143, ?-synuclein on Y39. The subsequent parkin inactivation leads to accumulation of the parkin substrates parkin interacting substrate (PARIS (ZNF746)) and aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2). c- Abl also phosphorylates PARIS on Y137 and AIMP2 on Y25. Each of these pathway molecules are potential biomarkers and/or part of a biomarker panel. Our hypothesis is that dysregulation of c-Abl signaling cascade is intrinsically linked to PD pathogenesis and that the relative phosphorylation state of downstream c-Abl substrates as well as activation of c-Abl itself should provide a sensitive read-out for the presence and/or the severity of PD. Using serum from participants in the Clinical Core?s Longitudinal Study and from our Udall Center Network collaborators we will set up a test and validation cohort. Aim 1 will then determine if these markers in the serum-derived L1CAM+ exosome are diagnostic of PD versus healthy controls and if these markers predict PD motor or cognitive progression. Using the same serum sources, Aim 2 will then determine if these markers in the serum-derived L1CAM+ exosome are diagnostic of PD versus other parkinsonisms. Taken together, this project will identify and validate the c-Abl pathway molecules as novel diagnostic/prognostic serum-based biomarkers that have the potential to provide clinicians with novel strategies for establishing a definitive diagnosis of PD and/or for monitoring the severity of disease in patients with PD.